Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/04—Antipruritics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents

Definitions

• the present invention relates to a preventive or therapeutic agent for pruritus.
• tricyclic compounds and their pharmaceutically acceptable salts having the activity to prolong the intervals of bladder contractions are known as therapeutic agents for urinary incontinence (WO97/14672 and WO98/46587).
• An object of the present invention is to provide a preventive or therapeutic agent for pruritus associated with allergic skin disorders or systemic disorders.
• the present invention relates to the following:
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, a tricyclic compound represented by Formula (I):
• R 1 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy or halogen
• X 1 —X 2 —X 3 represents CR 5 ⁇ CR 6 —CR 7 ⁇ CR 8
• R 5 , R 6 , R 7 and R 8 which may be the same or different, each represent hydrogen, substituted or unsubstituted lower alkyl, hydroxy, substituted or unsubstituted lower alkoxy, nitro, amino, mono(lower alkyl)-substituted amino, di(lower alkyl)-substituted amino, substituted or unsubstituted lower alkanoylamino or halogen]
• N(O) m ⁇ CR 6 —CR 7 ⁇ CR 8 (wherein R 6 , R 7 and R 8 each have the same significances as defined above, and m represents 0 or 1), CR 5 ⁇ CR 6 —N(O) m ⁇ CR 8 (wherein R 5 , R 6 , R 8 and m each have the same significances as defined above), CR 5 ⁇ CR 6 —CR
• Y represents —CH 2 S—, —CH 2 SO—, —CH 2 SO 2 —, —CH 2 O—, —CH ⁇ CH—, —(CH 2 ) p — (wherein p represents an integer of 0 to 2), —SCH 2 —, —SOCH 2 —, —SO 2 CH 2 — or —OCH 2 —; and
• R 2 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy, amino, mono(substituted or unsubstituted lower alkyl)-substituted amino, di(substituted or unsubstituted lower alkyl)-substituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkylamino, substituted or unsubstituted arylamino, or a substituted or unsubstituted heterocyclic group ⁇ or a pharmaceutically acceptable salt thereof,
• R 1 and X 1 —X 2 —X 3 each have the same significances as defined above;
• Y a represents —CH 2 SO 2 —, —SCH 2 —, —SOCH 2 —, —SO 2 CH 2 — or —OCH 2 —;
• R 2a represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy, amino, mono(substituted or unsubstituted lower alkyl)-substituted amino, di(substituted or unsubstituted lower alkyl)-substituted amino, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkylamino, substituted or unsubstituted arylamino, a substituted or unsubstituted heteroalicyclic group, or a substituted or unsubstituted nitrogen-containing heterocyclic group; and
• R 2a represents hydrogen, trifluoromethyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy, amino, mono(substituted or unsubstituted lower alkyl)-substituted amino, di(substituted or unsubstituted lower alkyl)-substituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkylamino, substituted or unsubstituted arylamino, a substituted or unsubstituted heteroalicyclic group, a substituted or unsubstituted nitrogen-containing heterocyclic group, or Formula (II):
• R 3 and R 4 which may be the same or different, each represent hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl, or R 3 and R 4 may be combined together with the adjacent carbon atom to form cycloalkyl; and Q represents hydroxy, substituted or unsubstituted lower alkoxy, amino or halogen).] or a pharmaceutically acceptable salt thereof,
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in (2), wherein Y a is —CH 2 SO 2 —, —SCH 2 —, —SOCH 2 — or —SO 2 CH 2 —,
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in (2), wherein Y a is —OCH 2 —,
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in any of (2) to (4), wherein R 1 is hydrogen, substituted or unsubstituted lower alkoxy or halogen,
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in any of (2) to (4), wherein R 1 is hydrogen,
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in any of (2), (5) and (6), wherein Y a is —CH 2 sO 2 —, —SO 2 CH 2 — or —OCH 2 —,
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in any of (2), (5) and (6), wherein Y a is —CH 2 SO 2 — or —SO 2 CH 2 —,
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in any of (2), (5) and (6), wherein Y a is —CH 2 SO 2 —,
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in any of (2) to (9), wherein X 1 —X 2 —X 3 is S—CR 7 ⁇ CR 8 (wherein R 7 and R 8 each have the same significances as defined above),
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in any of (2) to (9), wherein X 1 —X 2 —X 3 is CR 5 ⁇ CR 6 —CR 7 ⁇ CR 8 (wherein R 5 , R 6 , R 7 and R 8 each have the same significances as defined above),
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in any of (2) to (11), wherein R 2a is Formula (II):
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in (12), wherein n is 0,
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in (13), wherein R 3 is methyl, R 4 is trifluoromethyl, and Q is hydroxy,
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in (2), wherein R 1 is hydrogen, Y a is —CH 2 SO 2 —, X 1 —X 2 —X 3 is S—CR 7 ⁇ CR 8 (wherein R 7 and R 8 each have the same significances as defined above), and R 2 is Formula (III):
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, a tricyclic compound represented by Formula (Ib):
• Y b represents —CH 2 O—, —CH 2 S—, —CH 2 SO—, —CH ⁇ CH— or —(CH 2 ) P —(wherein p has the same significance as defined above);
• R 2b represents Formula (III):
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in (16), wherein X 1 —X 2 —X 3 is CR 5 ⁇ CR 6 —CR 7 ⁇ CR 8 (wherein R 5 , R 6 , R 7 and R 8 each have the same significances as defined above) or CR 5 ⁇ CR 6 —CR 7 ⁇ N (wherein R 5 , R 6 and R 7 each have the same significances as defined above),
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof describedin (16), wherein X 1 —X 2 —X 3 is CR 5 ⁇ CR 6 —O (wherein R 5 and R 6 each have the same significances as defined above) or CR 5 ⁇ CR 6 —S (wherein R 5 and R 6 each have the same significances as defined above),
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in (16), wherein X 1 —X 2 —X 3 is O—CR 7 ⁇ CR 8 (wherein R 7 and R 8 each have the same significances as defined above) or S—CR 7 ⁇ CR 8 (wherein R 7 and R 8 each have the same significances as defined above),
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in any of (16) to (19), wherein Y b is —CH 2 O—,
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in any of (16) to (19), wherein Y b is —(CH 2 ) n — (wherein p has the same significance as defined above),
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in (21), wherein p is 0,
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in (21), wherein p is 2,
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in any of (16) to (19), wherein Y b is —CH ⁇ CH—,
• a preventive or therapeutic agent for pruritus which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in any of (16) to (19), wherein Y b is —CH 2 S— or —CH 2 SO—, and
• the present invention also relates to the following:
• the lower alkyl includes, for example, straight-chain or branched lower alkyl groups having 1 to 8 carbon atoms, more specifically methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, 1,2,2-trimethylpropyl, heptyl, octyl, etc.
• the halogen means a fluorine, chlorine, bromine and iodine atom.
• the lower alkyl moiety of the lower alkoxy, mono(lower alkyl)-substituted amino and di (lower alkyl)-substituted amino has the same significance as that of the lower alkyl group mentioned above.
• the lower alkanoyl moiety of the lower alkanoylamino includes, for example, alkanoyl groups having 1 to 6 carbon atoms, more specifically formyl, acetyl, propanoyl, butanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, etc.
• the lower alkenyl includes, for example, straight-chain or branched lower alkenyl groups having 2 to 6 carbon atoms, more specifically vinyl, allyl, 1-propenyl, methacryl, 1-butenyl, crotyl, pentenyl, hexenyl, etc.
• the aryl and the aryl moiety of the arylamino include, for example, phenyl, naphthyl, etc; and the heteroaryl includes, for example, pyridyl, furyl, thienyl, quinolyl, imidazolyl, benzimidazolyl, thiazolyl, etc.
• the aralkyl moiety of the aralkylamino includes, for example, aralkyl groups having 7 to 12 carbon atoms, more specifically benzyl, phenethyl, naphthylmethyl, etc.
• the heterocyclic group includes, for example, heteroalicyclic groups, nitrogen-containing heterocyclic groups, etc.
• the heteroalicyclic group includes, for example, tetrahydrofuryl, tetrahydrothienyl, chromanyl, etc.
• the nitrogen-containing heterocyclic group includes, for example, heterocyclic groups containing one or two nitrogen atoms in the ring and optionally containing other hetero atoms such as oxygen, sulfur, etc.
• it includes pyrrolidinyl, pipecolinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, oxazolyl, etc.
• the substituted lower alkyl, the substituted lower alkoxy, the mono(substituted lower alkyl)-substituted amino, the di(substituted loweralkyl)-substituted amino, the substituted lower alkanoylamino and the substituted lower alkenyl each have 1 to a substitutable number (preferably 1 to 6, more preferably 1 to 4) of substituents which are the same or different.
• substituents include hydroxy, halogen, nitro, amino, mono(lower alkyl)-substituted amino, di(lower alkyl)-substituted amino, cycloalkyl, substituted cycloalkyl [the substituted cycloalkyl has 1 to 3 substituents which are the same or different, such as hydroxy, halogen, nitro, amino, mono(lower alkyl)-substituted amino, di(lower alkyl)-substituted amino, lower alkoxy, etc], aryl, substituted aryl (the substituent in the substituted aryl has the same significance as that in the substituted aryl described below), aralkyl, substituted aralkyl (the substituent in the substituted aralkyl has the same significance as that in the substituted aralkyl described below), lower alkoxy, substituted lower alkoxy [the substituted lower alkoxy has 1 to 3 substituents which are the same or different
• the two lower alkyl moieties on the same carbon atom of the substituted lower alkyl may form, together with the said carbon atom, an aliphatic ring.
• the number of the substituents may be, for example, 1 to 3 and the substituents may be the same or different.
• the substituent includes lower alkyl, substituted lower alkyl [the substituted lower alkyl has 1 to 3 substituents which are the same or different, such as hydroxy, halogen, nitro, amino, mono(lower alkyl)-substituted amino, di(lower alkyl)-substituted amino, lower alkoxy, etc], etc.
• the halogen has the same significance as defined above
• the lower alkyl and the lower alkyl moiety of the mono(lower alkyl)-substituted amino, di(lower alkyl)-substituted amino and lower alkoxy have the same significance as that of the above-described lower alkyl
• the aryl has the same significance as defined above.
• the cycloalkyl and the cycloalkyl moiety of aliphatic rings include, for example, cycloalkyl groups having 3 to 8 carbon atoms, more specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
• the aralkyl includes, for example, aralkyl groups having 7 to 12 carbon atoms, more specifically benzyl, phenethyl, naphthylmethyl, etc.
• the substituted aryl, the substituted heteroaryl, the substituted aralkylamino and the substituted arylamino each have 1 to 3 substituents which are the same or different.
• substituents includes lower alkyl, hydroxy, amino, halogen, etc.
• the substituted heterocyclic group has 1 to 3 substituents which are the same or different.
• substituents includes lower alkyl, hydroxy, halogen, etc.
• the lower alkyl includes, for example, straight-chain or branched lower alkyl groups having 1 to 6 carbon atoms, more specifically methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, 1,2,2-trimethylpropyl, etc.
• the halogen means a fluorine, chlorine, bromine and iodine atom.
• the lower alkyl moiety of the lower alkoxy, mono(lower alkyl)-substituted amino and di (lower alkyl)-substituted amino has the same significance as that of the lower alkyl group mentioned above.
• the lower alkenyl includes, for example, straight-chain or branched lower alkenyl groups having 2 to 6 carbon atoms, more specifically vinyl, allyl, 1-propenyl, methacryl, 1-butenyl, crotyl, pentenyl, hexenyl, etc.
• the aryl and the aryl moiety of the arylamino include, for example, phenyl, naphthyl, etc; and the heteroaryl includes, for example, pyridyl, furyl, thienyl, quinolyl, imidazolyl, benzimidazolyl, thiazolyl, etc.
• the aralkyl and the aralkyl moiety of the aralkylamino include, for example, aralkyl groups having 7 to 12 carbon atoms, more specifically benzyl, phenethyl, naphthylmethyl, etc.
• the heteroalicyclic group includes, for example, tetrahydrofuryl, tetrahydrothienyl, chromanyl, etc.
• the nitrogen-containing heterocyclic group includes, for example, a heterocyclic group containing one or two nitrogen atoms in the ring and optionally containing other hetero atoms such as oxygen and sulfur, in which the nitrogen atom in the ring bonds to the adjacent carbonyl group.
• it includes pyrrolidinyl, pipecolinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, oxazolyl, etc.
• the cycloalkyl includes, for example, cycloalkyl groups having 3 to 8 carbon atoms, more specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
• the substituted lower alkyl, the substituted lower alkoxy, the mono(substituted lower alkyl)-substituted amino, the di(substituted lower alkyl)-substituted amino, the substituted lower alkenyl and the substituted cycloalkyl each have 1 to 3 substituents which are the same or different.
• substituents include hydroxy, halogen, nitro, amino, mono(lower alkyl)-substituted amino, di(lower alkyl)-substituted amino, lower alkoxy, etc.
• the number of the substituents may be, for example, 1 to 3 and the substituents may be the same or different.
• the substituent includes lower alkyl, substituted lower alkyl [the substituted lower alkyl has 1 to 3 substituents which are the same or different, such as hydroxy, halogen, nitro, amino, mono(lower alkyl)-substituted amino, di(lower alkyl)-substituted amino, lower alkoky, etc], cycloalkyl, substituted cycloalkyl [the substituted cycloalkyl has 1 to 3 substituents which are the same or different, such as hydroxy, halogen, nitro, amino, mono(lower alkyl)-substituted amino, di(lower alkyl)-substituted amino, lower alkoxy, etc], aryl, substituted aryl [the substituted aryl has 1 to
• the substituted aryl, the substituted heteroaryl, the substituted aralkyl, the substituted aralkylamino and the substituted arylamino each have 1 to 3 substituents which are the same or different.
• substituents include lower alkyl, hydroxy, amino, halogen, etc.
• the substituted heteroalicyclic group and the substituted nitrogen-containing heterocyclic group each have 1 to 3 substituents which are the same or different.
• substituents include lower alkyl, hydroxy, halogen, etc.
• the pharmaceutically acceptable salts of Compound (I), Compound (Ia) and Compound (Ib) include pharmaceutically acceptable acid addition salts, for example, inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate and phosphate, and organic acid addition salts such as formate, acetate, benzoate, maleate, fumarate, succinate, tartrate, citrate, oxalate, glyoxylate, aspartate, methanesulfonate, ethanesulfonate and benzenesulfonate.
• inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate and phosphate
• organic acid addition salts such as formate, acetate, benzoate, maleate, fumarate, succinate, tartrate, citrate, oxalate, glyoxylate, aspartate, methanes
• the tricyclic compounds used in the present invention can be produced according to the methods disclosed in the above publications or similar methods, and can be isolated and purified by purification methods conventionally used in synthetic organic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization and various kinds of chromatography.
• a salt of the tricyclic compound used in the present invention in the case where it is produced in the form of the salt, it can be subjected to purification as such, and where it is produced in the form of a free base, it can be converted into a salt, after being dissolved or suspended in a suitable solvent, by adding an acid or a base thereto.
• tricyclic compounds or pharmaceutically acceptable salts thereof used in the invention may exist in the form of adducts with water or various solvents, which can also be used as active ingredients of the preventive or therapeutic agent of the invention.
• Test Example 1 The pharmacological activities of typical Compound (I) are described in test examples.
• the above compounds are referred to as Compound 1 and Compound 2, respectively.
• Test Examples 2 and 3 Compound 1 was used as a test compound.
• Compound 1 and Compound 2 are the same compounds as Compound (1-25) and Compound (3-12), respectively, described in WO98/46587.
• mice Male ddY mice each weighing 19 to 22 g (supplied by Japan SLC) were used in the test. 25 to 26 mice were put in each plastic cage and reared by allowing them to freely take commercially available solid feed and water, in an animal room at 19-25° C., 30-70% humidity and a 12 h lighting cycle (lighting: 7:00 a.m. to 7:00 p.m.) a day.
• Compound 1 and Compound 2 were separately suspended in aqueous 0.5 w/v % methyl cellulose solution to have a concentration of 3 mg/ml.
• the suspension of Compound 1 was further diluted with aqueous 0.5w/v % methyl cellulose solution, and suspensions or solutions for administration each having an intended concentration were prepared.
• the solvent (aqueous 0.5 w/v % methyl cellulose solution) or the suspension or solution for administration was orally administered to each mouse, 30 minutes before the subcutaneous injection of the compound 48/80, and its volume was 10 ml/kg.
• the solvent-administered mice were a control group.
• Every rat was shaven on the back, individually put in an acrylic monitor cage (200 ⁇ 145 ⁇ 170 mm), and acclimated therein for 30 minutes.
• 50 ⁇ l of a solution of poly-L-arginine (by Sigma) (4 mg of poly-L-arginine was dissolved in 1 ml of physiological saline) was intracutaneously injected into the interscapular region of each rat.
• poly-L-arginine by Sigma 4 mg of poly-L-arginine was dissolved in 1 ml of physiological saline
• the video was reproduced, and the number of the scratching by its back paws at around the area where the solution had been intracutaneously injected was counted for 30 minutes immediately after the intracutaneous administration.
• Each rat scratched itself a few times per about one second, and a series of these actions of each rat was counted as one.
• Compound 1 was suspended in aqueous 0.5 w/v % methyl cellulose solution to have a concentration of 0.1 or 1 mg/ml.
• the 0.1 mg/ml suspension of Compound 1 was further diluted with aqueous 0.5 w/v % methyl cellulose solution, and suspensions or solutions for administration each having an intended concentration were prepared.
• the solvent (aqueous 0.5 w/v % methyl cellulose solution) or the suspension or solution for administration was orally administered to each rat, 2 hours before the intracutaneous injection of poly-L-arginine, and its volume was 10 ml/kg.
• the solvent-administered rats were a control group.
• test compound was administered orally or intraperitoneally to three/group male dd mice (body weight: 20 ⁇ 1 g).
• the minimum lethal dose (MLD) was obtained by observing the mortality on the seventh day after the administration.
• MLD of Compound 1 was >1000 mg/kg by oral administration.
• compositions of the present invention can be produced by uniformly mixing an effective amount of Compound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient, with a pharmaceutically acceptable carrier. It is preferred that these pharmaceutical compositions are in a unit dose form suitable for administration such as oral administration or parenteral administration (including intravenous administration).
• any useful pharmaceutically acceptable carriers can be used.
• liquid preparations for oral administration such as suspensions and syrups can be produced using water, sugars such as sucrose, sorbitol and fructose, glycols such as polyethylene glycol and propylene glycol, oils such as sesame oil, olive oil and soybean oil, antiseptics such as p-hydroxybenzoates, flavors such as strawberry flavor and peppermint, or the like.
• Capsules, tablets, powders and granules can be produced using excipients such as lactose, glucose, sucrose and mannitol, disintegrators such as starch and sodium alginate, lubricants such as magnesium stearate and talc, binders such as polyvinyl alcohol, hydroxypropyl cellulose and gelatin, surfactants such as fatty acid esters, plasticizers such as glycerin, or the like. Tablets and capsules are the most useful unit dose forms for oral administration because of the easiness of administration. Solid pharmaceutical carriers are used for the production of tablets and capsules.
• Injections can be prepared using, for example, carriers comprising distilled water, a salt solution, a glucose solution or a mixture of salt water and a glucose solution. They are prepared as solutions, suspensions or dispersions using appropriate auxiliaries according to conventional methods.
• Compounds (I) or pharmaceutically acceptable salts thereof can be administered orally in the above pharmaceutical forms or parenterally as an injection or the like.
• the effective dose and administration schedule vary depending upon the mode of administration, the age, bodyweight and condition of a patient, or the like, but they are usually administered in a dose of 1 to 900 mg/60 kg/day, preferably 1 to 200 mg/60 kg/day.
• Capsules having the following composition were prepared according to a conventional method.
• Compound 1 500 g
• lactose 300 g
• light silicic acid anhydride 100 g
• sodium lauryl sulfate 100 g
• the resulting mixture was encapsulated in hard capsules No. 1 (content: 100 mg/capsule) using a capsule filler (LZ-64, Zanasi) to prepare capsules each containing 50 mg of the active ingredient.
• Compound 1 (1 g) is dissolved in 100 g of purified soybean oil, and 12 g of purified egg yolk lecithin and 25 g of glycerin for injection are added thereto. The resulting mixture is made up to 1000 ml with distilled water for injection, kneaded and emulsified according to a conventional method. The obtained dispersion is aseptically filtered using a 0.2 ⁇ m disposable membrane filter and aseptically packed in glass vials in 2 ml portions to prepare injections each containing 2 mg of the active ingredient per vial.
• the present invention provides a preventive or therapeutic agent for pruritus comprising, as an active ingredient, a tricyclic compound or a pharmaceutically acceptable salt thereof.

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• 2002
  • 2002-11-13 WO PCT/JP2002/011830 patent/WO2003041704A1/fr not_active Ceased
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